Biodegradable polyesters derived from aliphatic hydroxy carboxylic acids have been developed for medical applications such as surgical sutures, drug delivery devices, tissue supports, and implants for internal bone fixation (S. W. Shalaby and A. Johnson In: S. W. Shalaby, Editor, Biomedical polymers: Designed to degrade systems, Carl Hanser Verlag, Munich (1994), pp. 1-34. R. L. Dunn In: J. O. Hollinger, Editor, Biomedical applications of synthetic biodegradable polymers, CRC Press, Boca Raton (1995), pp. 17-31. V. Maquet and R. Jerome Mater. Sci. Forum 250 (1997), pp. 15-42).
Most of these materials are made from high-molecular-weight linear polyesters like polylactides, polyglycolides and their copolymers (D. E. Perrin and J. P. English In: A. J. Domb, J. Kost and D. M. Wiseman, Editors, Handbook of biodegradable polymers, Harwood Academic Publishers, Amsterdam (1997), pp. 3-27). Less attention has been paid to oligomeric esters, because these oligomers normally do not have the mechanical and thermal properties required for sutures or implants. Recent work on synthesis of liquid or low melt oligolactides offers interesting approach to a new class of biodegradable materials useful for injectable drug delivery systems, implant coatings or soft tissue augmentations. In addition, biodegradable polymer networks and composites can be prepared from these oligoesters terminated with unsaturated functional groups (D. K. Han and J. A. Hubbell Macromolecules 30 (1997), pp. 6077-6083, G. Coullerez, C. Lowe, P. Pechy, H. H. Kausch and J. Hilborn J. Mater. Sci: Mater. Med. 11 (2000), pp. 505-510).
Novel linear and star-shaped oligolactide macromers were prepared and used for the fabrication of highly porous polymer network scaffolds of controlled shape. In vitro studies on the cultivation of osteoblasts on these materials demonstrated that the polymer networks possess excellent biocompatibility and they are well suited as scaffolds for bone tissue engineering. (Matthias Schnabelrauch, Sebastian Vogta, Yves Larcherb and Ingo Wilkeb, Biomolecular Engineering, 19 (2-6), (2002), pp. 295-298).
Controlled ring-opening polymerization of L-Lactide was initiated using cyclic tin alkoxides which resulted in series of lactide macromonomers. Double bond of the initiator was successfully incorporated into the synthesized macromonomers which is well-suited for postpolymerization into a brushlike polymer. (Ryner, M.; Finne, A.; Albertsson, A. C.; Kricheldorf, H. R. Macromolecules 34, (2001) pp. 7281-7287). This unsaturated macromonomer provided a variety of opportunities for further modifications. The incorporated C═C double bond was oxidized into epoxides. (Finne, Anna; Albertsson, Ann-Christine. Journal of Polymer Science, Part A: Polymer Chemistry 42(3), (2004), pp. 444-452).
Poly (D, L) lactide diacrylate macromer was used to develop a new family of biodegradable hydrogels with photo-crosslinked dextran derivative of allyl isocyanate. The changes in thermal and mechanical properties of these hydrogels as function of dextran and lactide macromer composition were investigated. (Zhang, Yeli; Chu, Chih-Chang. Journal of Materials Science: Materials in Medicine 13(8), (2002), pp. 773-781).
A series of temperature and pH-sensitive hydrogels based on poly (2-ethyl-2-oxazoline) and three-arm poly (D, L-lactide) macromer were synthesized via photo-copolymerization. Lactide macromer was synthesized by first reacting lactide with Glycerol and then reacting 3 arm poly-lactide with methacryloyl chloride and triethylamine. This study effectively proved that unique combination of water swellability and biodegradability properties provides hydrogels for a much wider range of applications in biomedical fields. (Wang, Chau-Hui; Hsiue, Ging-Ho. Journal of Polymer Science, Part A: Polymer Chemistry 40(8), (2002), pp. 1112-1121).
Difunctional oligolactone macromers were synthesized by ring-opening oligomerization of various lactones (L-lactide, glycolide, p-dioxanone) in the presence of suitable diols (propane-1,2-diol, dianhydro-D-glucitol) and subsequent end capping of these oligolactones with methacrylate moieties. Highly porous scaffolds were fabricated from these macromers. The oligolactide based polymer networks possess excellent biocompatibility and are promising candidates as scaffolds in bone tissue engineering. (Haris, Parvez I.; Vogt, S.; Berger, S.; Wilke, I.; Larcher, Y.; Weisser, J.; Schnabelrauch, M. Bio-Medical Materials and Engineering 15(1, 2), (2005), pp. 73-85).
Weak polyacids or polybases, which undergo an ionization/deionization transition from pH 4˜8, are utilized as pH-responsive polymers. Poly(N,N′-dimethyl amino ethyl methacrylate) (PDMAEMA) and poly(N,N′-diethyl amino ethyl methacrylate) (PDEAEMA) are examples of pH responsive polybases. (Eun Seok Gil, Samuel M. Hudson. Prog. Polym. Sci. 29 (2004) pp. 1173-1222). They have amine groups in their side chains. The amine groups gain protons under acidic condition and release them under basic condition. PDMAEMA was also reported to exhibit temperature sensitivity similar to PNIPAAm (M. Okubo, H. Ahmad and T. Suzuki, Colloid Polym Sci 276 (1998), pp. 470-475). The origin of the thermo-responsive behavior lies in the balance of hydrophobicity and hydrophilicity of poly (DMAEMA), while the pH-sensitive behavior is due to the existence of tertiary amino-group, which gets protonated with decreasing pH of the aqueous medium. These properties of poly (DMAEMA) were used to develop hydrogels having good mechanical properties through copolymerization of DMAEMA with other methacrylate derivatives, among which the copolymers and hydrogels prepared from DMAEMA and Butyl methacrylate (BMA) were studied in detail. By using a unique method and photoredox system to initiate the copolymerization of DMAEMA with BMA, a stable asymmetric bilayer sheet which shows reversible thermal and pH-responsive behavior was developed as intelligent soft material. (Li, Fu-Mian; Chen, Shuang-Ji; Du, Fu-Sheng; Wu, Zhi-Qiang; Li, Zi-Chen. ACS Symposium Series 726 (1999), pp. 266-276).
A pH-sensitive interpolymer polyelectrolyte complex was synthesized by gamma radiation induced copolymerization of acrylic acid and N,N′-Dimethyl amino ethyl methacrylate (DMAEMA). pH dependent swelling showed different phase transitions depending on the copolymer composition and also showed the interpolymer polyelectrolyte complex formation at pH values ranging from pH 3 to pH 4. The ability of the copolymer to be used as drug carrier for colon specific drug delivery system was demonstrated using Ketoprofen as a model drug. (El-Hag Ali Said, Amr. Biomaterials 26(15), (2005), pp. 2733-2739).
A new pH/temperature responsive polymer system with transitions resulting both from polymer-water and polymer-polymer interactions has been demonstrated using the copolymer composed of N,N′-dimethyl amino ethyl methacrylate (DMAEMA) and ethylacrylamide (EAAm) and the mixture of poly DMAEMA and poly EAAm. Based on the pH/temperature responsiveness of the copolymer and polymer mixture, glucose controlled insulin delivery system and microspheres for temperature sensitive solute release were designed and characterized. (Yuk, Soon Hong; Seo, Jung Ki; Lee, Jin Ho; Cho, Sun Hang. ACS Symposium Series 752 (2000), pp. 232-242).
The insulin release from the same copolymer matrix was demonstrated. (Yuk, Soon Hong; Cho, Sun Hang; Lee, Sang Hoon. Polymer Preprints 39(2), (1998), pp. 204-205). Poly(N,N-dimethyl amino ethyl) methacrylate (DMAEMA) and polyethyl acrylamide (EAAm) system was also used to design the microspheres for pH/temperature sensitive drug release. Hydrocortisone was used as a model drug. This gave the control of hydrocortisone release in an on-off manner without considerable lag time (Kim, E. J.; Cho, S. H.; Yuk, S. H. Biomaterials 22(18), (2001), pp. 2495-2499).
In the same way copolymers of DMAEMA and ethylacrylamide (EAAm) [or acrylamide (AAm)] were prepared and characterized as polymeric drug delivery systems modulated for pulsatile and time release. When the temperature of poly DMAEMA aqueous solution was increased above 50° C., the polymer precipitated from the solution. The incorporation of EAAm in the copolymer caused lower critical solution temperature (LCST) to shift to a lower temperature. This was because of the formation of hydrogen bonds, which protect (N,N-dimethyl amino) ethyl groups from exposure to water and led to a hydrophobic contribution to the LCST. Glucose controlled insulin release and thermosensitive permeation of hydrocortisone was accomplished by manipulating pH/temperature responsiveness of polymers. (Yuk, Soon Hong; Cho, Sun Hang; Lee, Sang Hoon; Seo, Jung Ki; Lee, Jin Ho. Editor(s): Ottenbrite, Raphael M.; Kim, Sung Wan. Polymeric Drugs & Drug Delivery Systems (2001), pp. 39-55).
The effect of pendent side-chain length and crosslinking agent concentration in methyl methacrylates/dimethyl amino ethyl methacrylate as polybasic/hydrophobic pH-sensitive hydrogel was studied. Increasing both side-chain length and crosslinking agent concentration decreased the sharpness of response to pH and water-uptake capacity of the polymer. (Falamarzian, M.; Varshosaz, J. Drug Development and Industrial Pharmacy 24(7), (1998), pp. 667-669).
Amphiphilic comb-copolymers made by copolymerization of N, N-dimethyl amino ethyl methacrylate (DMAEMA) and poly (Butyl acrylate) macromonomers are excellent dispersants for many organic pigments in different coating systems. (Muehlebach, Andreas. Polymeric Materials Science and Engineering 90, (2004), pp. 180). The glucose-responsive insulin controlled release system based on the hydrogel poly (2-hydroxyethyl methacrylate-co-N, N-dimethyl amino ethyl methacrylate), with entrapped glucose oxidase, catalase and insulin was studied. When exposed to physiological fluids, glucose diffuses into the hydrogel; glucose oxidase catalyzes the glucose conversion to gluconic acid, causing swelling of the pH-sensitive hydrogel and subsequently increased insulin release. The effects of polymer morphology and oxygen availability on hydrogel swelling and on insulin release kinetics were tested. In vivo experiments on rats demonstrated that at least some of the entrapped insulin retained its active form and was effective in reducing blood glucose levels. Thus the pH-sensitive hydrogel poly (HEMA-co-DMAEMA) could be manipulated to produce glucose-responsive insulin release system that was effective in reducing blood glucose levels. (Traitel, Tamar; Cohen, Yachin; Kost, Joseph. Biomaterials 21(16), (2000), pp. 1679-1687).
Copolymerization of acrylate monomers with basic monomers like Dimethyl amino ethyl methacrylate (DMAEMA) with the aim of designing controlled drug delivery of therapeutic or complex protein molecules like insulin or site specific drug delivery using hydrogels has been reported. Such polymers containing basic functional groups such as amino groups are known to dissolve at pH prevalent in the stomach. Hence these copolymers of acrylates with DMAEMA result in pH sensitive polymers and at times exhibit temperature sensitive behavior. The copolymers have high molecular weights and they are used in variety of applications like drug delivery systems and also as dispersants in pigment industry. DMAEMA along with other neutral methacrylates (Composition of Eudragit E) is also used as reverse enteric coating. This polymer shows swelling at pH 5. Percentage of DMAEMA in Eudragit E is high (35% w/w), which possibly results in negative drug interaction with some of the drugs. (M. J. Alonso, M. L. Lorenzo-Lamosa, M. Cuna, J. L. Vila-Jato and D. Torres, Journal of Microencapsulation, 1997, Volume 14, No. 5, 607-616). Low molecular weight DMAEMA polymers having low basic monomer content and their utility as excipient in pharmaceutical drug delivery has not been investigated in the past.
The preferred embodiments relate to a composition of a low molecular weight macromer based copolymer synthesized using oligomeric lactide macromer and basic monomer. It also demonstrates that at very low concentration of the basic monomer (about 12% w/w) this copolymer exhibits unusual dissolution behavior. Contrary to the solubility behavior of Eudragit E polymers, these polymers are soluble over a wide pH range. These polymers are copolymers of lactide macromer and DMAEMA. Because of their unusual dissolution behavior, they can be used as excipients in pharmaceutical drug delivery systems. The lactide macromer used in the preferred embodiments is a low molecular weight moiety and the copolymer shows unexpected dissolution properties which are very different than copolymers of DMAEMA reported in the literature.